Combinations to reprogramme CD8+ T cells - PowerPoint Presentation

1. Combinations to reprogramme CD8+ T cellsCombining immunotherapeutic agents to achieve ARV-free remission of HIVAsier Sáez-Cirión, PhD, Institut Pasteur, Paris, France @asiersc

2. MSD : MSDAVENIR research grant to RHIVIERA (pVISCONTI study)ViiV Healthcare: research grant to RHIVIERAMSD, Gilead, ViiV healthcare, Janssen: speaker feesConflict of interest disclosure

3. CD8+ T cells contribute to partially control HIV infection, but have limitationsTemporal correlation between resolution of acute viremia and appearance of HIV-specific CD8+ T cells Koup, et al. JV 1994; Borrow, et al. JV 1994.Depletion of CD8+ T cells during SIV infection leads to increased viral loadJin, et al. JEM 1999; Schmitz, et al. Science 1999.Viral load can be contained in the presence of certain MHC class I HLA (e.g. HLA-B27 and HLA-B57)Migueles, et al. PNAS 2000; Goulder, et al. Nat. Med. 1997.Selective pressure by CD8+ T cells leads to escape mutationGoulder, et al. Nat. Med. 1997; Borrow, et al. Nat. Med. 1997; Price, et al. PNAS 1997.Goulder and Watkins. 2004. Nat Rev ImmunolHowever, a minority of people can spontaneously control HIV to undetectable levels: HIV controllers (HIC)

4. CD8 T cell responses in natural controllers and non controllers Survival and self-renewalMultipotencyBroad antiviral activityHigh cytotoxic potentialLymphoid homingShort-livedLimited expansion capacitySkewed differentiationLimited cytolytic activityProne to exhaustionPeripheral homingCollins et al. Nat Rev Immunol 2020; Rutishauser and Trautmann, Curr Opin HIV/AIDS 2022

5. The difference may be in the memory, and set very earlyEarly differences observed in the phenotype of virus-specific memory CD8+ T cells despite similar viral loadsExpansion of central memory CD8+ T cells over-time in controllersMemory CD8 T cells in controllers: ↑CD127 ↑TCF1 ↓T-betRutishauser RL. et al. JCI Insight, 2020Sekine T. et al. Sci. Immunol, 2020.Passaes et al. Cell Reports 2020Non controllerHIV controller

6. Early ART initiation promotes an efficient “secondary”SIV-specific CD8+ T cell responseSuperior SIV-suppressive activity of CD8+ T cells expanded against rebounding virus than against virus in primary infectionCentral memoryEffector memoryCentral memoryEffector memoryPassaes et al UnpublishedpVISCONTI study

7. Picking the optimal path for T cell differentiation GSK3 inhibitorsIL-15effectormemory IikeDysfunctional memoryprecursorReprogrammingPrimingReprogrammingcGAMP

8. Reprogram CD8+ T cells to enhance mitochondrial and antiviral activitiesIncreased magnitude of HIV response and abrogated glucose dependencyChao et al Front Immunol 2017Van der Windt 2012IL-15 induces mitochondria neogenesisP=0.008P=0.06P=0.008P=0.94HIVCMVIL-15 enhanced mitochondrial activityEnhanced HIV suppressive capacity5.8%16.6%5.0%16%9.7%19.1%Expansion of short-lived effector cellsAngin et al. Nat Metabol 2019Perdomo-Celis, unpublishedMathieuAngin

9. Reprogram CD8+ T cell to enhance their stemnessMaintenance of memory like profile of CD8+ T cells after stimulationPerdomo Celis et al JCI 2022mTORC1mTORC2Promotion of TNF-α and maintenance of other effector activities

10. Reprogram HIV-specific CD8+ T cell response from non-controllers: enhanced memory and antiviral potentialLess differentiated memory subsetsIncreased effector potentialSurvivalExpansionRestricted activation of mTORC1 pathwayPerdomo Celis et al JCI 2022

11. Reprogram HIV-specific CD8+ T cell response from non-controllers: enhanced HIV suppressive capacityPerdomo Celis et al JCI 2022

12. Reprogrammed CD8+ T cells respond better to homeostatic γ-chain cytokinesReprogrammed HIV-specific CD8+ T cells : enhanced homeostatic proliferation in response to IL-15Reprogrammed cells express higher levels of IL-7 and IL-15 receptorsReprogrammed cells enhanced responsiveness to IL-7 and IL-15Rochman et al, Nat Rev Immunol 2009Perdomo Celis et al JCI 2022

13. Enhancing CD8+ T-cell priming: learning from HIV-2 Collaboration: V Appay, N ManelConstruction of HIV-1 and HIV-2 virusCarrying the Melan-A peptide.Lissina J Immunol 2016HIV-2 ↑ DNA synthesis in DC  ↑Innate immune activation in DCs through cGASLahaye Immunity 2013Cabral-Piccin et al SubmittedHIV-2 prime a superior response with distinct signature

14. Activation of the type I IFN response during priming contribute to enhanced CD8 T cellsCabral-Piccin et al SubmittedPolyfunctionalityFunctional avidity

15. CD8+ T cells from HIV controllers and non controllers have divergent memory profiles since early infectionHIV controllers’ memory cells  metabolic plasticity, primed for survival, enhanced antiviral potentialOptimal memory appears key to ensure progressive maturation of CD8+ T cell responseEx vivo metabolic reprogramming reinvigorates HIV-specific CD8+ T cell responses from non-controllers: enhanced memory, expansion and antiviral potential CD8 T cell reprogramming may constitute a new therapeutic opportunity to achieve HIV remissionSummaryReprogrammed CD8+ T cells: - long-term survival capacity, greater expansion, enhanced response to homeostatic cytokines, ability to give rise to all memory and effector subsetsOne of the current challenges of ACT is to improve the persistence and durability of the responseAdoptive cell therapies?Unmodified or CAR T cells

16. ANRS CO21 CODEXANRS CO6 “PRIMO”CHU BicetreOlivier LambotteNicolas NoelAntoine CheretCecile GoujardJean-François DelfraissyAlain VenetCamille LécurouxINSERM U1018Laurence MeyerFaroudy BoufassaAsma Essat Samia HendouAzeb TadesseVolunteers and physicians who participate to our studiesHIV inflammation and persistenceViral Reservoirs and ControlIDMITRoger Le GrandBruno VaslinNathalie Dereuddre-BosquetDelphine DesjardinImmunoconceptVictor Appay Mariela PiccinLaura PapagnoInstitut Curie Nicolas ManelXavier LahayeCHU NeckerVeronique Avettan-FenoelChristine RouziouxAdeline MélardStevenn Volant Marie-Agnès DilliesMathieuAnginJC Valle-CasusoAcknowledgements1UM1AI164562-01 Michaela Müller-TrutwinEmory UniversityMirko PaiardiniDeanna GulpaGuido SilvestriWeill Cornell MedicineR Brad Jones